Composition and method for the treatment of onychomycosis in animals

ABSTRACT

This invention relates to a composition and method for the treatment of white line disease, including ailments such as onychomycosis, sporotichosis, hoof rot, jungle rot,  pseudallecheria boydii , scopulariopsis or athletes foot. The composition of the present invention is useful for the treatment of fungal infections such as onychomycosis in warm blooded animals such as humans and horses. The method of the present invention is directed to the application of a therapeutic amount of the present composition.

RELATED APPLICATIONS

[0001] This application is a divisional of co-pending application Ser.No. 09/545,486 which claims the priority filing date of the Provisionalapplication serial No. 60/128,604, Apr. 8, 1999.

FIELD OF THE INVENTION

[0002] This invention relates to a composition and method for theprevention and treatment of fungal infections such as sporotrichosis,onychomycosis infections, hoof rot, jungle rot, pseudallecheria boydii,scopulariopsis, athletes foot, canker sole and fungal infectionsgenerally. The composition of the present invention is useful for thetreatment of fungal infections in warm-blooded animals such as humansand horses. The method of the present invention is directed to theapplication of a therapeutic amount of the present composition.

BACKGROUND OF THE INVENTION

[0003] Conditions such as onychomycosis and other fungal infections poseserious problems in dermatology. It has been estimated that theprevalence of onychomycosis in the general population is in the range of2-13% and increases to about 15-20% in the 40-60 year old age group.Onychomycosis is a condition recognized by discoloration beneath toenails and finger nails along with pain when pressure is placed near orat the site of discoloration. The condition usually affects more thanone nail. Various fungi, classified as white superficial fungi, causethe condition. Frequently the condition is treated by the combination ofnail avulsion and application of a pharmaceutical agent. Presentlyavailable topical antifungal formulations for treating fungal infectionshave been met with limited success. This is primarily due to the limitedability of such compounds to penetrate into the nail plate, which ishyperkeratotic. The treatment of the condition is further problematic ingeriatric patients where therapeutic options are often limited due topossible drug interactions, systemic side effects of treatment, andcontraindications secondary to other medical ailments.

[0004] The treatment of fungal infections of the nail and hoof generallyfalls into three categories: systemic administration of antifungals;surgical removal of all or part of the nail or hoof followed by topicaltreatment of the exposed tissue; or topical application of conventionalcreams, lotions, gels or solutions, frequently including the use ofbandages to keep these dosage forms in place on the nail or hoof. All ofthese approaches have major drawbacks.

[0005] Long term systemic (oral) administration of an antifungal agentfor the treatment of onychomycosis is often required to produce atherapeutic effect in the nail bed. For example, oral treatment with theantifungal compound ketoconozole typically requires administration of200 to 400 mg/day for 6 months before any significant therapeuticbenefit is realized. Such long term, high dose systemic therapy can havesignificant adverse effects. For example, ketoconozole has been reportedto have liver toxicity effects and reduces testosterone levels in blooddue to adverse effects on the testes. Patient compliance is a problemwith such long term therapies especially those which involve seriousadverse effects. Moreover, this type of long term oral therapy isinconvenient in the treatment of a horse or other ruminants afflictedwith fungal infections of the hoof.

[0006] Accordingly, the risks associated with parenteral treatmentsgenerate significant disincentive against their use and considerablepatient non-complience. However, these and other related hindrances totreatment can be potentially avoided through the appropriate use of atherapeutically effective of a composition according to the presentinvention. Moreover, the present invention provides a method for theadministration of an effective amount of the present inventioncomprising the application of the composition to an area in need oftreatment and maintaining the composition in contact therewith for aneffective period of time.

[0007] Surgical removal of all or part of the nail followed by topicaltreatment also has severe drawbacks. The pain and discomfort associatedwith the surgery and the undesirable cosmetic appearance of the nail ornail bed represent significant problems, particularly for femalepatients or those more sensitive to physical appearance. Generally, thistype of treatment is not realistic for ruminants such as horses.

[0008] Topical therapy has significant problems too. Topical dosageforms such as creams, lotions, gels etc., can not keep the drug inintimate contact with the infected area for therapeutically effectiveperiods of time. Bandages have been used to hold drug reservoirs inplace in an attempt to enhance absorption of the pharmaceutical agent.However the bandages are thick, awkward, troublesome and generally leadto poor patient compliance.

[0009] Hydrophilic and hydrophobic film forming topical antifungalsolutions have also been developed. These dosage forms provide improvedcontact between the drug and the nail, but the films are not occlusive.Topical formulations for fungal infection treatment have largely triedto deliver the drug to the target site (an infected nail bed) bydiffusion across or through the nail.

[0010] Nail is more like hair than stratum corneum with respect tochemical composition and permeability. Nitrogen is the major componentof the nail attesting the to the nail's proteinaceous nature. The totallipid content of mature nail is 0.1-1.0%, while the stratum corneumlipid is about 10% w/w. The nail is 100-200 times thicker than thestratum corneum and has a very high affinity and capacity for bindingand retaining antifungal drugs. Consequently little if any drugpenetrates through the nail to reach the target site. Because of thesereasons topical therapy for fungal infections have generally beenineffective.

[0011] Compounds known as penetration or permeation enhancers are wellknown in the art to produce an increase in the permeability of skin orother body membranes to a pharmacologically active agent. The increasedpermeability allows an increase in the rate at which the drug permeatesthrough the skin and enters the blood stream. Penetration enhancers havebeen successful in overcoming the impermeability of pharmaceuticalagents through the skin. However, the thin stratum corneum layer of theskin, which is about 10 to 15 cells thick and is formed naturally bycells migrating toward the skin surface from the basal layer, has beeneasier to penetrate than nails. Moreover, known penetration enhancershave not proven to be useful in facilitating drug migration through thenail tissue.

[0012] Antimicrobial compositions for controlling bacterial and fungalinfections comprising a metal chelate of 8-hydroxyquinoline and an alkylbenzene sulfonic acid have been shown to be efficacious due to theincreased ability of the oleophilic group to penetrate the lipoid layersof micro-cells. The compounds however, do not effectively increase theability to carry the pharmaceutically active antifungal through thecornified layer or stratum corneum of the skin. U.S. Pat. No. 4,602,011,West et al., Jul. 22, 1986; U.S. Pat. No. 4,766,113, West et al., Aug.23, 1988.

[0013] The composition of the present invention is directed a method andcomposition for treating onychomychosis, and related infections, inanimals. Because onychomychosis is an infection afflicting all animalswith a nail or hoof, this composition is useful in the treatment of anyanimal with a nail or hoof.

[0014] Onychomychosis is a fungal infection of the nail or hoof bed.Because the infection is under the nail or hoof it is very dificult totreat. Traditional methods of treatment involve complete nail removal inhumans. Not infrequently the chosen treatment regime involves nailremoval combined with topical treatment of the now exposed infectedtissue. However, the removal of an infected hoof requires completeimobilization of the animal, an often impossible task. This treatmentregime is therefore unreasonable for the treatment of hoofed animals,such as horses.

[0015] Topical treatments have also been employed. However, because thenail is largely impervious to the transfer of drugs, little of theapplied drug reaches the infected tissue. This problem is morepronounced in hoofed animals where the nail is many time thicker thanthe nail of a human.

[0016] However if white line disease is allowed to grow unchecked, itcan result in the crippling of the animal. The unbchecked growth of thefungus in humans often inflicts substantial pain.

[0017] The inventor has solved the problem of treating a human afflictedwith onychomychosis, without surgery. Moreover, the present inventionsolves this long felt need through the formulation of a compositionwhich has unique properties relative to migration into the infectedsite.

[0018] It would therefore be useful to provide a composition for thetreatment of onychomychosis and related infections in animals.

[0019] It would further be useful to provide a mehtod for theadministration of the present composition for the treatment ofonychomychosis in animals.

DESCRIPTION OF THE INVENTION

[0020] These and other objects of the invention are accomplished througha method of treatment of the infected nail or hoof and a composition tobe applied to the infected nail/hoof comprising a composition consistingessentially of a compound according to firmula I:

[0021] Where R¹ is hydrogen;

[0022] R³ is hydroxy;

[0023] R² is hetero;

[0024] each R⁷ is independently hydrogen, alkyl, hetero, heteroalkyl,aryl or heteroaryl and;

[0025] a copper composition;

[0026] a peroxide;

[0027] a polyhydroxy aromatic compound;

[0028] a transition metal coordination complex;

[0029] all dissolved in water, wherein the composition contains greaterthan 100 mg copper composition.

[0030] The composition according to the present invention is directed tothe treatment of fungal infections in animals comprising:

[0031] at least one element such as an element selected from columns Iathrough column VIa of the periodic chart of the elements, preferably anelement selected from columns IIa through column IVa and most preferablya transition metal selected from the group comprising column IIIb tocolumn IIb and where the element is in ionic form. The element in ionicform means an element in a state other than its elemental state, suchCu⁺² or Cu⁺¹ or Ag⁺¹. The element in ionic form can be from any source,but usually from the oxide, carbonate, hydroxide or other salt of theelement such as CuSO₄, CuO, CuOH₂ or Ag₂SO₄.

[0032] at least one chelating or complexing agent selected from thegroup consisting of a carboxylic acid, hydroxyaryl carboxylic acid,thioaryl carboxylic acid, a heteroaryl carboxylic acid, a heteroatomsubstituted aryl carboxylic acid, a hydroxy heteroaryl carboxylic acid,crown ether, hetero crown ether, tributyl tin oxide, thiol, diamine,triamine, glycols thioglycols and aminoglycols.

[0033] In the composition according to this invention the metal, thechelating or complexing agent and optionally a peroxide are combined ina polar solvent at a suitable temperature and for a suitable period oftime to allow the solvation of the added ingredients.

[0034] Although not wanting to be bound by any theory or presentedhypothesis, a brief analysis of the chemistry involved may be useful inunderstanding the invention.

[0035] It is known that transition metals are cytotoxic if introducedinto a cell. For example, 12 is bactericidal when applied topically, andthe use of metallic copper as an antibiotic is also known. It istherefore believed that the introduction of a toxic metal into thecellular system of the fungal organism will cause it to die. The presentinvention seems to cause, or at least assists in the introduction of ametal into the cellular system of the fungus. This is accomplishedthrough the formation of a chelate, complex or salt between a metal andan organic agent such as salicylic acid or thiosalicylic acid andadministering this composition to the infected site. The formation ofany one specific chelate or complex structure is not essential for theproper functioning of the composition nevertheless, a complex ofundetermined structure is likely formed in solution. In this regard, itis desirable that the amount of the complexing agent be in greateramounts than the metal in the composition, e.g. that the complexingagent and the metal be in a ratio of greater than 1:1, complexingagent:metal.

EXAMPLES Example 1

[0036] The treatment solution was prepared by adding about 100-300 gramsof salicylic acid to 4 Liters of warm water. This was followed by 10-100g NaOH and 1-60 grams of boric acid. The solution was mixed and filteredto remove traces of undissolved material. Then about 1-100 grams ofcopper sulfate where added and the solution became a light green.Finally, the solution was diluted to 20 L with water.

Example 2

[0037] To 1 liter of water is added 20 grams of thiosalicylic acid and0.5 grams copper sulfate. The solution is stirred sufficiently to allowproper mixing. The solution changes from blue to amber, indicating thatan association with the copper and the complexing agent has formed.

Example 3

[0038] The treatment solution was prepared by adding about 230 grams ofsalicylic acid to 4 Liters of warm water. This was followed by 45 g NaOHand 25 grams of boric acid. The solution was mixed and filtered toremove traces of undissolved material. Then 10 grams of copper sulfatewhere added and the solution became a light green. The solution wasallowed to cool and 1-100 mL of hydrogen peroxide was added. Finally,the solution was diluted to 20 L with water.

Example 4

[0039] The treatment solution was prepared by adding about 230 grams ofsalicylic acid to 4 Liters of warm water. This was followed by 45 g NaOHand 25 grams of boric acid. The solution was mixed and filtered toremove traces of undissolved material. Then 50 grams of copper sulfatewhere added and the solution became a light green. The solution wasallowed to cool. Finally, the solution was diluted to 20 L with water.

[0040] Salts of any metal may be used but water soluble metal salts arepreferred and water soluble salts of Ag, Cu, Ni and Co are mostpreferred.

[0041] An organic moiety complexing agent such as an aryl carboxylicacid, a hydroxyaryl carboxylic acid and a thioaryl carboxylic acid arepreferred and salicylic acid and thiosalicylic acid are most preferred.

[0042] The inclusion of a peroxide, although optional, may be includedfrom the group comprising: organic and inorganic peroxides such ashydrogen peroxide, benzoyl peroxide and acetyl peroxide.

[0043] The above fungal infection treating composition is applied in anymanner that places the composition is contact with the infected tissue.One method of application involves the use of a syringe with out theneedle. A syringe of suitable size is loaded with the composition andsprayed or squirted in the space between the hoof of the infected animaland the attach tissue. Substantial amounts of black, decayed tissue androtting matter may be discharged after the first washing. A secondapplication is recommended to ensure the delivery of adequate amounts ofthe fungal treating composition to the infected tissue.

[0044] The infected area may also be treated through the use of clothsoaked in the fungal treating composition of the present invention. Forexample, a cloth soaked in the composition may be inserted into thespace between the hoof and the attached tissue so that the soaked clothis in intimate contact with the infected tissue, thereby placing thefungal treating composition in contact with the infected tissue.

[0045] In general the infected tissue may be treated in any method ormanner that causes the infected tissue to be contacted with the fungaltreating composition of this invention.

1. A composition for the treatment of an animal afflicted withonycomychosis, the composition comprising:

Where R¹ is hydrogen, alkyl, hetero, heteroalkyl, aryl or heteroaryl; R³is hydroxy, alkyl, hetero, heteroalkyl, aryl or heteroaryl; R² ishetero; each r⁷ is independently hydrogen, alkyl, hetero, heteroalkyl,aryl or heteroaryl and; a copper composition; a peroxide; a polyhydroxyaromatic compound; a transition metal coordination composition; alladmixed in a hydrophyllic carrier composition.
 2. The compositionaccording to claim 1 wherein R² is oxygen.
 3. The composition accordingto claim 2 wherein the copper composition is a copper complex.
 4. Thecomposition according to claim 3 wherein the copper complex is a diaminepolymer-copper complex.
 5. The composition according to claim 1 whereinthe coordination composition is a Co chelate or complex.
 6. Thecomposition according to claim 1 wherein the coordination composition isa Zn chelate or complex.
 7. The composition according to claim 1 whereinthe coordination composition is a Fe chelate or complex.
 8. Thecomposition according to claim 1 wherein the polyhydoxy aromaticcompound is a 1,2,4,5-tetra hydroxy benzene.
 9. The compositionaccording to claim 1 wherein the peroxide is an organic peroxide. 10.The composition according to claim 1 wherein the peroxide is aninorganic peroxide.
 11. The composition according to claim 1 wherein theperoxide is hydrogen peroxide.
 12. The composition according to claim 1wherein the hydrophyllic carrier is between about 50% to about 99% byweight water.
 13. The composition according to claim 1 wherein thehydrophyllic carrier is between about 1% to about 50% a compoundaccording to formula II

wherein R⁴ is a heteroatom, R⁵ is a heteroalkyl or heteroatom-H and R⁶is —CH₃,alkylaryl, aryl or heteroaryl and n and x are independentlybetween 1 and
 20. 14. The composition according to claim 1 wherein thehydrophyllic carrier is between about 0.1% to about 30% by weightalcohol.
 15. A pharmaceutical composition for the topical treatment ofonychomychosis comprising a composition according to claim 1 and apharmaceutically acceptable carrier.
 16. A method for the treatment ofwhite line disease comprising: applying to an afflicted area thewhiteline treating composition according to claim
 1. 17. the methodaccording to claim 16 further comprising cleaning of the afflicted areaprior to application of the whiteline treating composition.
 18. Themethod according to claim 17 wherein cleaning of the afflicted areaconsists essentially of debrideing.
 19. A method of preventing whitelinedisease comprising the steps of: a) applying to a site in need oftreatment a suitable amount of a whiteline treating compositionaccording to claim 1; b) applying to the site a barrier composition. 20.The method according to claim 19 wherein the barrier composition is abarrier to water.
 21. The method according to claim 19 wherein thebarrier composition is a barrier to oxygen.
 22. The method according toclaim 19 further comprising cleaning the site prior to application ofthe whiteline treating composition.
 23. The method according to claim 22wherein the cleaning of the site comprises the steps of: i) applying acleaning composition to the afflicted area; ii) causing at least apartial removal of the afflicted tissue.
 24. The method according toclaim 23 wherein steps I and ii are repeated.
 25. The method accordingto claim 23 wherein the cleaning composition is a surfactant.
 26. Themethod according to claim 23 wherein the cleaning composition containsan enzymatic composition.